Back pain is the second most common ailment complained about in doctors' offices after the common cold and is responsible for some 100 million lost days of work annually in the United States alone. A major proportion of these back injuries result from disorders of the intervertebral discs in the spine. Although the exact pathogenesis of many intervertebral disc disorders is unknown, disorders such as degenerative disc disease are generally mechanically induced and biologically mediated.
The IVD consists of an outer annulus fibrosus (AF), which is rich in collagens that account for its tensile strength, and an inner nucleus pulposus (NP), which contains large proteoglycans (PGs) that retain water for resisting compression loading. Biologically, disc cells in both the AF and NP maintain a balance between anabolism and catabolism, or steady state metabolism, of their extracellular matrices (ECMs), and are modulated by a variety of substances including cytokines, enzymes, their inhibitors and growth factors such as insulin like growth factor (IGF), transforming growth factor β (TGF-β), and bone morphogenetic proteins (BMPs). Various enzymes, such as matrix metalloproteinases (MMPs), and cytokines, mediate the catabolic process, or breakdown of the matrix. The degeneration of an IVD is thought to result from an imbalance between the anabolic and catabolic processes, or the loss of steady state metabolism, that are maintained in the normal disc.
In a normal IVD, the ECM of the NP is synthesized and maintained throughout adult life by relatively few cells. In the adult human, most NP cells are chondrocyte-like, whereas NP cells in the young have a significant number of large notochordal cells. It is not known if both NP cell types synthesize the large-molecular-weight hydrophilic PG, termed aggrecan, which constitutes the most abundant molecule in the tissue. These aggrecan molecules interact extracellularly with long linear strands of hyaluronan (HA), forming aggregates that become entangled in a fibrillar network made up principally of type II collagen. The swelling, fluid and ion-transport properties, as well as the intrinsic mechanical properties of the collagen-aggrecan solid matrix govern the deformational behavior of the NP. The collagen network gives the tissue tensile strength and hinders expansion of the viscoelastic, under-hydrated, aggrecan molecules that provide compressive stiffness and enable the tissue to undergo reversible deformation.
The AF contains a relatively homogeneous population of chondrocyte-like cells that synthesize a matrix richer in collagen and poorer in PG than cells from the NP, although the presence of different populations of cells and the zonal differences of matrix metabolism is suggested. Importantly, some of the AF cells synthesize PG and collagen molecules not normally found in significant amounts in cartilage. The progressive loss of the PG content of the IVD, with subsequent dehydration of the NP, has been implicated in the pathogenesis of IVD degeneration.
Unfortunately, current treatment of intervertebral disc disorders, including IVD degeneration, has been limited to only a few courses of action, the most common of these being spinal surgery. Even though in some cases spinal surgery achieves over 90% good to excellent results, the pathological IVD, with time, continues to undergo degeneration and significant disability may still result. Furthermore, although surgical techniques such as lumbar spinal fusion have a high success rate if performed on patients with deformities or documented instabilities such as spondylolisthesis and scoliosis, the outcome of surgical procedures for low back pain without radiculopathy is unpredictable.
In addition to often being unable to predict the outcome, there are a number of drawbacks to surgical procedures such as spinal fusion. First, the ability of the bone to heal or “fuse” varies; the average success rate of a lumbar spinal fusion is approximately 75%-80%. Unfortunately, the failure of fusion may be associated with continued symptoms. Second, a spinal fusion at one or more levels causes stiffness and decreased motion of the spine. Third, having a spinal fusion at one or more levels will cause more stress to be transferred to adjacent levels. Transferred stress may cause new problems to develop at other levels, leading to additional back surgery. For these reasons, numerous investigators are working on alternative treatments to spinal fusion including intradiscal electrothermal therapy (IDET), disc prostheses, and biological repair.
While some of the alternatives to spinal fusion show promise, there are still many disadvantages. For example, although IDET may relieve discogenic pain in patients, it does not restore structure or the biological matrices of the disc. As another example, the use of disc prostheses in disc replacement requires a surgical procedure and its associated potential surgical morbidities. In addition to the potential complications associated with undergoing surgery and general anesthesia, complications associated with artificial disc replacement may include breakage of the metal plate, dislocation of the implant, and infection. Like joint replacement surgery, artificial implants may fail over time due to wear of the materials and loosening of the implants.
What is needed is a non-invasive method that can result in the restoration of structure of the IVD. Currently, there are no non-invasive methods, such as treatment using pharmaceuticals that can accomplish these goals. Steroids are currently used to treat intervertebral disc disorders but steroids have many significant drawbacks in that they only control the symptoms of IVD degeneration and do nothing to stop, prevent, or reverse further injury.
Because of the drawbacks of steroid use, recent interest for the treatment of IVD disorders has focused on pharmaceuticals that can treat or prevent IVD disorders by targeting certain IVD biochemical mechanisms. The biochemistry of the IVD plays an important role in its mechanical properties. The NP is able to maintain its fluid pressure to balance the high external loads on the IVD because of the abundance of negatively charged PGs. This molecular meshwork of PGs entrapped in a collagen network endows the IVD with both compressive stiffness and tensile strength. One of the biological strategies for IVD repair is to enhance the synthesis of PGs and collagen, which may restore biomechanical function of the matrix.
In the IVD, the ECM content of PGs and the synthesis of PGs by chondrocytes embedded in the ECM decreases markedly with age and degeneration. Several cytokines [i.e. interleukin-1, (IL-1)] and proteinases [i.e., stromelysin and other MMPs] have been detected in degenerated or herniated IVDs. Interleukin-1α also stimulates the production of some of the MMPs, nitric oxide and prostaglandin E2 by normal IVD cells while inhibiting PG synthesis. Misregulation of these inflammatory cytokines and proteases likely contribute to IVD disorders such as IVD degradation. A strategy for biological treatment of IVD disorders such as intervertebral disc degeneration is to halt or counteract these cytokines by delivering inhibitors or other substances that block their enzymatic or catabolic activities. For example, IL-1 receptor antagonist (IL-1 Ra) has been investigated as a candidate to block IL-1 function in the IVD. Another strategy for biological treatment includes treating or preventing IVD disorders by preventing the expression of the genes that encode the proteins active in IVD disorders. One way to block the expression of these genes is to block the transcription factors that act upon them.
For example, the matrix metalloproteinase genes are generally controlled by several transcription factors including transcription factors that act on the PEA3 and AP-1 transcription factor sites. See Chakroborti et al. MOL CELL BIOCHEM 253: 269-285 (2003). One example of a transcription factor that plays a critical role in the regulation of many genes that control many of the biochemical factors active in IVD disorders such as the Matrix Metalloproteinases, is Nuclear Factor—kappa B (NF-κB), a complex group of heterodimeric and homodimeric transcription factors. Members of the NF-κB family include NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB, and c-Rel. These molecules are trapped in the cytoplasm as an inactive complex by IκB, Dissociation of the transcription factor NF-κB from this complex has been reported to play a pivotal role in the regulation of inflammatory cytokine production, by inducing a coordinated transactivation of such genes as TNFα, IL-1, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GMCSF), metalloproteinases and intercellular adhesion molecule 1 (ICAM-1). In rheumatoid arthritis (RA), the activation of NF-κB in synovium has been observed.
It has been hypothesized that blocking NF-κB family members may be able to reduce the degradation of articular cartilage tissue. The addition of NF-κB decoy oligonucleotides (ODN) by intraarticular injection in the bilateral hind ankle joints of collagen-induced arthritis (CIA) rats using the hemagglutinating virus of Japan (HVJ)-liposome method has shown a decrease in the severity of hind-pay swelling and a marked suppression of joint destruction. Unfortunately, rat articular ankle cartilage differs substantially from the fibrocartilage found in the human intervertebral disc. Inhibition of NF-κB has not been shown to prevent or treat fibrocartilage degradation in any species. Likewise, inhibition of NF-κB has not been shown to have biological effects on human primary fibrochondrocytes, specifically human primary fibrochondrocytes in vitro.
It has been hypothesized that blocking certain enzymes and cytokines believed to be active in IVD disorders at a transcriptional level may be used in the prevention or treatment of IVD disorders. Nevertheless, until the present invention there were no effective pharmaceuticals that acted using this principle.